Abstract
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations.
Highlights
Brain disorders with a vascular and/or neurodegenerative component affect one billion people worldwide, according to the World Health Organization
These regulatory RNAs include long ncRNAs, which target pathogenic genes directly involved in the disease or epigenetically regulated genes, small interference RNAs, piwi RNAs, and microRNAs
A genome-wide methylation analysis of Parkinson’s disease (PD) with quantitative DNA methylation levels of 27,500 CpG sites corresponding to 14,495 genes showed a significant methylation decrease of the CYP2E1 gene with the corresponding mRNA overexpression in brains from PD patients, suggesting that epigenetic variants of this cytochrome contribute to PD susceptibility [257] (Table 2). These results suggest that altered methylation of CYP2E1 in PD may contribute to the individual susceptibility and help to explain the conflicting findings with regard to environmental toxins and genetic vulnerability [257]
Summary
Brain disorders with a vascular and/or neurodegenerative component affect one billion people worldwide, according to the World Health Organization. Detection of the first symptomatic features normally occurs after a high rate of cell death and damaged tissue, which significantly affect brain function and hinders potential treatments In this regard, novel epigenetically-based treatments are gaining a great interest as a potential novel treatments for complex multigenic neurodegenerative diseases [3,13,14,15,16,17]. Current pharmacological treatments for PD are based on restoring the dopamine levels using different strategies: (i) increase dopamine availability by treatments with dopamine precursors, such as L-DOPA (levodopa), or dopaminergic agonists (amantadine, apomorphine, bromocriptine, lisuride, cabergoline, pergolide, pramipexole, ropinirole, and rotigotine) and (ii) inhibition of dopamine catabolism or degradation, by using monoamine-oxidase B (MOB) inhibitors, such as rasagiline and selegiline, or catechol-O-methylatransferase (COMPT) inhibitors, such as entacapone and tolcapone All these pharmacological treatments only provide a symptomatic relief rather than stopping or delaying the progression of the disease. Combination of current drugs with novel compounds, especially bioproducts seem to reduce these clinical complications and provide dopaminergic neuroprotection in order to enhance dopaminergic neurotransmission and reduce premature neurodegeneration [17]
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